Abstract
Recombinant nematode anticoagulant protein c2 (rNAPc2) is a specific inhibitor of tissue factor (TF)/factor VIIa complex with novel antithrombotic activity. TF is highly expressed in human colorectal tumors, and levels are positively correlated with disease progression. To explore the therapeutic potential and mechanism of action of rNAPc2 during tumor growth and metastasis, we tested rNAPc2 in several experimental colorectal cancer models in mice. Administration of rNAPc2 inhibited pulmonary metastasis in mice systemically disseminated with CT26 murine colon carcinoma cells in a dose-dependent fashion. Combining rNAPc2 with the cytotoxic agent 5-fluorouracil or bevacizumab (humanized anti-vascular endothelial growth factor monoclonal antibody) resulted in additive growth inhibition and simultaneous reduction of microvessel density in HCT116 human colorectal tumor xenografts in nude mice. Furthermore, rNAPc2 potentiated CPT-11 in inhibiting hepatic metastasis in nude mice with portal vein injection of HCT116 tumor cells. Long-term administration of rNAPc2 significantly suppressed spontaneous formation of intestinal tumors in Apc(Min/+) mice. Using a RNA interference approach, we showed that TF expression is necessary for rNAPc2-mediated inhibition of HCT116 human colorectal tumor xenograft growth in nude mice, indicating that the antitumor effect of rNAPc2 may be transduced through TF that is expressed on tumor cells. rNAPc2 is a potent anticancer agent when used in combination with chemotherapy or antiangiogenic therapy in mouse models of colorectal cancer, and TF positivity appears to be required for its activity.
Highlights
Recombinant nematode anticoagulant protein c2 is a specific inhibitor of tissue factor (TF)/factor VIIa complex with novel antithrombotic activity
To study the antimetastatic activity of Recombinant nematode anticoagulant protein c2 (rNAPc2), we injected CT26 murine colon carcinoma cells into the tail vain of syngeneic mice. rNAPc2 was given as daily intraperitoneal injections to mice immediately after CT26 cell dissemination until the time of lung tissue harvest
These results suggest that rNAPc2 significantly reduces lung metastasis in syngeneic mice with systemic dissemination of CT26 mouse colon carcinoma cells
Summary
Recombinant nematode anticoagulant protein c2 (rNAPc2) is a specific inhibitor of tissue factor (TF)/factor VIIa complex with novel antithrombotic activity. RNAPc2 potentiated CPT-11 in inhibiting hepatic metastasis in nude mice with portal vein injection of HCT116 tumor cells. Conclusions: rNAPc2 is a potent anticancer agent when used in combination with chemotherapy or antiangiogenic therapy in mouse models of colorectal cancer, and TF positivity appears to be required for its activity. We tested the antitumor potential of rNAPc2, a potent and specific inhibitor of the TF/fVIIa complex, in several colorectal cancer models in mice. We have shown that rNAPc2 additively inhibits the growth of primary and metastatic tumors when used in combination with chemotherapy or antiangiogenic therapy in mice with xenografted, disseminated, or spontaneous colorectal cancer cells. Expression of TF in colorectal cancer cells appears to be necessary for the rNAPc2-mediated tumor-inhibitory effect in mice
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